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Drugs used in hypertensive diseases in pregnancy

Sven Monta´ n
Purpose of review
This review will summarize results derived from the most recent
publications on the use of drugs in women with hypertensive
diseases in pregnancy.
Recent findings
There is consensus that severe hypertension should be treated
without delay to reduce maternal risks of acute cerebrovascular
complications. There is no consensus that mild antihypertensive
drugs improve maternal or fetal outcome in mild moderate
hypertension. Evidence exists that antihypertensive drugs may
halve the risk of severe hypertension in pregnancy. No proof
exists that antihypertensive drugs reduce perinatal mortality or
development of preeclampsia, and such drugs have not been
associated with improved fetal growth. Clinical trials indicate
non-consistent data concerning antihypertensive treatment on
antenatal rate of hospitalization, proteinuria at delivery and
neonatal respiratory distress syndrome. Hydralazine has for
many years been regarded as the first drug of choice for
treatment of severe hypertension in pregnancy. Recent findings
indicate that the calcium antagonist nifedipine might be a better
alternative. Angiotensin converting enzyme inhibitors and
angiotensin II receptor antagonists should be discontinued due
to fetotoxicity especially when prescribed in the first trimester.
The b1-selective adrenoceptor blocker atenolol in the first
trimester is associated with low birth weight.
Large randomized controlled trials are urgently needed to
determine whether antihypertensive therapy in pregnancy
results in greater benefit than risks for mother and fetus.
hypertension, pregnancy, drugs, human, complication
Curr Opin Obstet Gynecol 16:000–000. # 2004 Lippincott Williams & Wilkins.
Department of Obstetrics and Gynaecology, Lund University, Malmo¨ University
hospital, Malmo¨ , Sweden
Correspondence to Sven Monta´ n, Associate Professor, Department of Obstetrics and
Gynaecology, SE-205 02 Malmo¨ , Sweden
Tel: +46 40 33 21 25; fax: +46 40 96 26 00; e-mail:
Current Opinion in Obstetrics and Gynecology 2004, 16:000–000
# 2004 Lippincott Williams & Wilkins
Hypertensive disorders are seen in about 7–10% of human
pregnancies. Hypertension is associated with increased
maternal and fetal mortality and morbidity. Mild chronic
hypertension is associated with 33% of preterm deliveries
and 11% of small-for-gestational-age infants. For
severe chronic hypertension (systolic blood pressure
4180 mmHg or diastolic blood pressure 4110 mmHg)
preterm delivery is seen in about 62–70% of pregnancies
and small-for-gestational-age infants in 40% [1.]. Preeclampsia
is generally regarded as a more dangerous
complication than gestational or chronic hypertension.
However, severe gestational hypertension is associated
with higher rates of preterm delivery and small-forgestational-
age infants than mild gestational hypertension
or mild preeclampsia [2.]. Delivery is the final treatment
of hypertensive disorders of pregnancy, but if preeclampsia
occurs early in pregnancy induction of labour with
close monitoring of mother and fetus seem to give better
results than immediate caesarean section delivery [3].
The cause of preeclampsia is probably multifactorial and
is still unknown. Immunologic disturbancies have been
suggested [4–6]. The value of antihypertensive treatment
of mild to moderate hypertension remains to be shown.
With better understanding of the pathophysiologic
process improved results would be expected with the
use of drugs for prophylactic or antihypertensive treatment.
Recent findings concerning different drugs used to
treat hypertension will be reviewed.
Preeclampsia is characterized by increased peripheral
vascular resistance, reduced plasma volume, endothelial
cell activation, impaired glomerular filtration rate and
renal plasma flow, reduced prostacyclin activity, increased
production of thromboxane AII in placenta and
platelets, vasoconstriction in the uterine and spiral
arteries and increased vascular permeability.
Blood velocity in the middle cerebral arteries of women
with chronic hypertension was measured with transcranial
Doppler ultrasound and results were compared with
those for patients with chronic hypertension and superimposed
preeclampsia [7]. The absolute cerebral perfusion
pressure was higher in the women with
superimposed preeclampsia. The women with superimposed
preeclampsia had a higher mean value of
cerebral perfusion pressure measured as multiples of
the standard deviation from the mean value for normal
pregnancy, despite there being no blood pressure
difference. Drugs used to treat preeclamptic women
DOI: ????????????????? 1
might have unpredictable effects on cerebral perfusion.
Therefore, baseline measurement of cerebral perfusion
pressure might facilitate a more scientifically correct
decision of which antihypertensive drug to use.
Platelet activation was studied in 30 women with
preeclampsia, 30 women with gestational hypertension,
20 women with essential hypertension, 30 women with
normotension and 30 non-pregnant women [8]. Platelet
activation was similar in all pregnancy groups except in
preeclampsia. This may be part of the pathophysiologic
process in preeclampsia, but is not predictable by the
platelet count and is not apparent in all women with
preeclampsia. Drugs reducing platelet aggregation and
consumption would therefore be beneficial in pregnancy
in established or impending preeclampsia.
Prophylactic treatment
Promising results have been published concerning use of
calcium, low dose aspirin and magnesium sulphate to
prevent preeclampsia.
Calcium supplementation
Effect of calcium supplementation to prevent pregnancy-
induced hypertension and preeclampsia was
reviewed in a meta-analysis [9.]. Calcium supplementation
during pregnancy reduced the risk of preeclampsia
compared with placebo (RR 0.35; 95% CI 0.20–0.60).
The effects were greatest for women at high risk of
hypertension (OR 0.22; 95% CI 0.12–0.42) and in
women with low baseline calcium intake (OR 0.29;
95% CI 0.16–0.49).
Calcium supplementation reduced the risk of having a
baby lighter than 2500 g (RR 0.45; 95% CI 0.22–0.95). A
modest reduction in systolic and diastolic blood pressure
was also observed with calcium supplementation (RR
0.58; 95% CI 0.43–0.79). Women at risk of pre-eclampsia
should therefore consider taking calcium, but a positive
impact on maternal and fetal morbidity has not been
Antiplatelet drugs
Antiplatelet drugs (mainly aspirin) versus placebo or no
treatment significantly reduce the risk of preeclampsia in
women considered to be at risk for the condition (RR
0.85; 95% CI 0.78–0.92), premature delivery before 37
completed weeks of gestation (RR 0.92; 95% CI 0.88–
0.97), and death of the baby (RR 0.86; 95% CI 0.75–
098). The benefit was greatest for women given more
than 75 mg aspirin per day. No significant differences
were observed in other important outcomes. There was
no significant difference in the relative risk reduction
between women at high and low risk for preeclampsia
and its complications [10]. No evidence exists that
aspirin increases the risk of bleeding for mother or baby.
A metaanalysis with pooling of results from five
controlled trials in women with abnormal uterine artery
Doppler in the second trimester confirmed the beneficial
effects of aspirin in reducing the rate of preeclampsia
(OR 0.55; 95% CI 0.32–0.95) [11].
One hundred and twenty women considered to be at
high risk of preeclampsia were screened by transvaginal
Doppler ultrasound at 12–14 weeks [12.]. Ninety
women with bilateral uterine artery notches were
recruited in a randomized, double blind, placebocontrolled
trial to study the efficacy of low dose aspirin
(0.5 mg /kg/day, the dose adjusted at a follow up visit if
the weight of the women exceeded the initial weight by
at least 10%) to prevent pregnancy induced hypertension
and intrauterine growth retardation. Treatment with low
dose aspirin, initiated at 12–14 weeks of gestation,
reduced the frequency of pregnancy induced hypertension
(RR 0.31; 95% CI 0.13–0.78) and preeclampsia (RR
0.2 95% CI 0.05 to 0.86) and hypertension before 37
weeks (RR 022; 95% CI 0.05–0.97) [12.]. No adverse
effects on mother or infant was noted. Previously, the
large Clasp trial demonstrated that low-dose aspirin is
safe for the fetus and newborn infant [13].
Magnesium sulphate
One systematic review [14] and one large randomized
controlled trial [15.] demonstrated that prophylactic
magnesium sulphate halves the risk of eclampsia in
women with severe preeclampsia compared with placebo
(RR 0.41; 95% CI 0.29–0.58). The trials found no
evidence of a difference between magnesium sulphate
and placebo for rate of stillbirth or perinatal mortality in
babies born to women with severe preeclampsia.
Magnesium sulphate might reduce maternal mortality
compared with placebo (RR 0.54; 95% CI 0.26–1.10).
Magnesium sulphate was associated with flushing in 20%
and respiratory depression in 1% (0.5% with placebo).
Among other adverse effects, a metaanalysis of five
randomized placebo controlled trials found that magnesium
sulphate slightly increased caesarean section rates
compared with placebo (RR 1.05; 95% CI 1.01–1.10)
There is unequivocal evidence that magnesium sulphate
is superior to other agents in reducing recurrent
eclamptic fits. In 33 countries, 10 141 women with
preeclampsia were randomized to either magnesium
sulphate or placebo treatment to prevent eclamptic
convulsions [15.]. Women treated with magnesium
sulphate had a 58% lower risk of eclampsia (95% CI
40–71) than those who received placebo treatment.
Maternal mortality was non-significantly lower among
women allocated magnesium sulphate (RR 0.55; 95% CI
0.26–1.14). Substantial harmful effects to mother or baby
have not been demonstrated in the short term.
Maternal-fetal medicine 2
The value of magnesium sulphate to prevent disease
progression in 222 women with mild preeclampsia was
evaluated in a randomized placebo controlled trial [16..].
Patients with chronic hypertension or severe preeclampsia
were excluded. Magnesium sulphate does not have a
major impact on disease progression and does not seem
to increase rates of caesarean delivery, infectious
morbidity, obstetric haemorrhage, or neonatal depression.
Antihypertensive drugs
Thirteen randomized controlled trials were reported as
having inadequate power to rule in or out benefits
concerning antihypertensive treatment on maternal or
fetal well-being. Information is scarce on the frequency
of adverse effects attributable to antihypertensive
agents. Possible adverse effects of antihypertensive
drugs in mild chronic hypertension include fetal renal
failure when angiotenson-converting enzyme inhibitors
are used in the second or third trimester and growth
retardation when atenolol is used early in pregnancy
[17]. Thus, as all antihypertensive drugs pass the
placental barrier, safety considerations are important for
clinicians who prescribe antihypertensive treatment for
mild hypertension during pregnancy. Overall, antihypertensive
treatment in pregnancy reduces the risk of
severe hypertension. No proof exist that antihypertensive
drugs reduce perinatal mortality or the development
of preeclampsia, and such drugs have not been
associated with improved fetal growth [18].
Beta-adrenoceptor blockers
Oral beta-blockers for mild to moderate hypertension
during pregnancy have specifically been evaluated in the
Cochrane database [19.]. Oral beta-blockers decrease the
risk of severe hypertension (RR 0.37; 95% CI 0.26–0.53;
11 trials; n = 1128 women) and the need for additional
antihypertensive drugs (RR 0.44; 95% CI 0.31–0.62;
seven trials; n = 856 women). Beta-blockers seem to be
associated with an increase in small-for-gestational-age
infants (RR 1.36; 95% CI 1.02–1.82; 12 trials; n = 1346
women). Maternal hospital admissions may be decreased,
frequency of neonatal bradycardia increased
and respiratory distress syndrome decreased. Treatment
with beta-blockers compared with methyldopa treatment
appear to be no more effective and probably equally safe
The effect of the selective b-1-adrenoceptor blocker,
atenolol, on maternal disease, preterm delivery and fetal
growth has been evaluated [20]. Early intervention with
atenolol was associated with a low rate of severe maternal
hypertension and preterm delivery. The failure to adjust
therapy in response to an excessive fall in cardiac output
or increase in vascular resistance was associated with
reduced fetal growth.
Atenolol taken at the time of conception or during the
first trimester of pregnancy was associated with low birth
weight [21.]. This finding was independent of the
development of superimposed preeclampsia. Use of
atenolol in the second trimester did not cause the same
effect and was not different in its effects from the other
antihypertensive drugs. Development of superimposed
preeclampsia is the overriding effect in the reduction of
infant birth weight in the second trimester. It was
concluded that atenolol used in the first trimester could
be pharmacologically programming these infants to
restricted growth patterns (Table 1).
Calcium channel blockers
The efficacy and safety of calcium channel blocker
10 mg nifedipine tablets was randomly compared with
rapid onset and short-acting 10 mg nifedipine capsules
for the treatment of women with acute severe hypertension
(4170/110 mmHg) in the second half of pregnancy
[22]. Nifedipine capsules lowered blood pressure further
than nifedipine tablets. A second dose of nifedipine was
required twice as often with tablets (P = 0.05), but fewer
women had hypotensive episodes with tablets
(P = 0.001). Fetal distress was uncommon with capsules
and tablets. Thus, nifedipine tablets although slower of
onset, are as effective as capsules for the rapid treatment
of severe hypertension.
The blood pressure lowering effects in severe hypertensive
patients beyond 24 weeks of gestation and
side-effects were compared between intravenously
administered nicardipine and labetalol [23]. Treatment
was administered to achieve a 20% blood pressure
lowering effect. The success rates were similar with the
two drugs although nicardipine caused significantly
Table 1. Oral antihypertensive drugs with widespread use in
total daily dose
CNS a-adrenoceptor stimulant
Methyldopa 750 mg to 2 g Three times daily
Beta-adrenoceptor blocker
Atenolola 25–100 mg Once to twice
Metoprolol 50–100 mg Twice daily
Pindololb 2.5–20 mg Twice daily
Alpha and b-adrenoceptor blocker
Labetalol 100–400 mg Two to three times
Calcium channel blockers
Nifedipine 10–40 mg Twice daily
Isradipine 2.5–30 mg Two to three times
CNS, central nervous system. aTo be used with caution in first trimester
due to increased risk of low birth weight. bWith intrinsic sympathomimetic
Drugs used in hypertensive diseases 3
greater systolic and diastolic blood pressure decreases.
Both drugs were well tolerated except for moderate
tachycardia with nicardipine.
A randomized controlled trial in severe preeclamptic
women with a gestational age of more than 20 weeks
compared nifedipine 8 mg in drops sublingually with
hydralazine 5–10 mg intravenously [24..]. The initial
dose of hydralazine was 5 mg followed by further doses
of 10 mg. All patients received magnesium sulphate
treatment. Fewer nifedipine treated patients required
more than three doses (9.3%) compared with hydralazine
treated patients (19.7%; P = 0.03). The mean urine
output was greater in the nifedipine treated group than
in those treated with hydralazine: 50% more before
delivery and 34% more after delivery. Nifedipine was
found to significantly delay development of hypertensive
crisis compared with hydralazine (median time for
hypertensive crisis 3.1 h for nifedipine versus 2.1 h for
hydralazine; P = 0.005). Sublingual nifedipine in drops
might be a more appropriate antihypertensive drug for
women with severe preeclampsia.
According to the Cochrane Database System Review the
choice of antihypertensive drug for treatment of severe
hypertension in pregnancy should depend on the
experience and familiarity of an individual clinician with
a particular drug, and what is known about maternal and
fetal side-effects. Diazoxide (risk of hypotension), and
kentaserin (less effective than hydralazine) are drugs that
probably are not good choices [25].
To individualize antihypertensive treatment in severe
hypertension in pregnancy, I personally prefer intravenous
administration of hydralazine, diluted in saline
starting with a low initial stat dose of 2.5 mg. This dose
can be repeated after 15–20 min if no blood pressure
lowering effect is observed. A reduction of the diastolic
blood pressure by 10–15 mmHg is safe and in most cases
adequate and minimizes the need for plasma volume
expansion. If the expected blood pressure level still is
not reached following three or four stat doses of 2.5 mg
hydralazine, I would prefer to put up a hydralazine drip.
In my clinical experience, of more than 20 years, I have
never observed hypotension or abnormal fetal heart rate
patterns in association with intravenously administered
2.5 mg hydralazine in stat doses.
Other randomized controlled studies in women with
severe preeclampsia would be urgently needed to
confirm the interesting findings that sublingual administration
of nifedipine drops might be a better alternative
to hydralazine (Table 2).
Oligura or anuira in pregnancies or following childbirth
in preeclamptic or eclamptic women is a dangerous
complication. The effects of continuous furosemide and
low-dose dopamine infusion were compared in women
with preeclampsia/eclampsia and oliguria in the postpartum
period [26]. Hypovolaemia was corrected under
central venous pressure monitoring and urine output
monitored for 4 h. Administration of continuous infusion
of furosemide showed comparable efficacy to low-dose
dopamine infusion in ameliorating oliguria in severe
preeclampsia/eclampsia after delivery (Table 1).
Drugs to avoid
Five cases of fetal or neonatal deaths have been reported
following maternal use of sartans, angiotensin II
antagonists, for hypertension. A case of transient renal
failure was reported following telmisartan therapy during
pregnancy. This class of antihypertensive medication
should be avoided during pregnancy and breast feeding
[27]. Treatment in the second or third trimester with
angiotensin converting enzymes inhibitors in women
with pre-existing chronic hypertension has been associated
with fetal renal failure [17].
Low dose aspirin has small to moderate benefits when
used for prevention of preeclampsia. Magnesium sulphate
halves the risk of eclampsia in women with
preeclampsia and reduces the risk of recurrent convulsions.
Large randomized controlled trials are urgently
needed to determine whether antihypertensive therapy
in mild to moderate hypertension pregnancy results in
greater benefit than risks for mother and fetus. Further
studies are also needed to confirm the best drug of
choice for acute treatment of severe hypertension in
pregnancy from the short and long-term perspectives.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
. of special interest
.. of outstanding interest
Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol 2002;
This presents an expert’s view of the present knowledge on management of
chronic hypertension in pregnancy.
Table 2. Different alternatives for acute antihypertensive treatment
in pregnancy
Drug Dose
Dihydralazine 2.5–5 mg intravenously, repeat after 15–20 min if
necessary or 0.5–10 mg/h by infusion
Labetalol 20 mg intravenously, then 20–80 mg every 20–30 min
if necessary or, 0.5 mg/min by infusion
Nifedipine 8–10 mg sublingual, repeat after 20–30 min then
10–20 mg every 3–6 h up to a total dose of 1 mg/kg
body weight
Maternal-fetal medicine 4
Buchbinder A, Sibai BM, Caritis S, et al. Adverse perinatal outcomes are
significantly higher in severe gestational hypertension than in mild preeclampsia.
Am J Obstet Gynecol 2002; 186:66–71.
This study indicated that all pregnancies with hypertension, with or without
proteinuria, should be carefully monitored.
3 Coppage KH, Polzin WJ. Severe preeclampsia and delivery outcomes: Is
immediate cesarean delivery beneficial? Am J Obstet Gynecol 2002;
4 Wang JX, Knottnerus A-M, Schuit G, et al. Surgically obtained sperm, and
risk of gestational hypertension and pre-eclampsia. Lancet 2002; 359:673–
5 Wimalasundera RC, Larbalestier N, Smith JH, et al. Preeclampsia,
antiretroviral therapy, and immune reconstitution. Lancet 2002; 360:1152–
6 Lynch A, McDuffie R, Murphy J, et al. Preeclampsia in multiple gestation: the
role of assisted reproductive technologies. Obstet Gynecol 2002; 99:445–
7 Belfort MA, Tooke-Miller C, Allen JC, et al. Pregnant women with chronic
hypertension and superimposed pre-eclampsia have high cerebral prefusion
pressure. BJOG 2001; 108:1141–1147.
8 Harlow FH, Brown MA, Brighton TA, et al. Platelet activation in hypertensive
disorders of pregnancy. Am J Obstet Gynecol 2002; 187:688–695.
Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during pregnancy
for preventing hypertensive disorders and related problems. Cochrane
Database Syst Rev. 2002;(1):CD001059.
An interesting survey of why and when to recommend calcium supplementation to
patients at risk.
10 Knight M, Duley L, Henderson-Smart DJ, King JF. Antiplatelet agents for
preventing and treating pre-eclampsia. Cochrane Database Syst Rev.
11 Coomarasamy A, Papaioannou S, Gee H, Khan KS. Aspirin for the
prevention of preeclampsia in women with abnormal uterine artery Doppler:
a meta-analysis. Obstet Gynecol 2001; 98:861–866.
Vaino M, Kujansuu E, Iso-Mustaja¨ rvi M, Ma¨ enpa¨ a¨ J. Low dose acetylsalicylic
acid in prevention of pregnancy-induced hypertension and intrauterine growth
retardation in women with bilateral uterine artery notches. BJOG 2002;
A method to select patients among women at high risk of pre-eclampsia or
intrauterine growth retardation for prophylactic prevention of pre-eclampsia is
13 CLASP Collaborative Group. CLASP: a randomised controlled trial of lowdose
aspirin for the prevention and treatment of pre-eclampsia among 9 364
pregnant women. Lancet 1994; 343:619–629.
14 Duley L, Gulmezoglu AM, Henderson-Smart D. Magnesium sulphate and
other anticonvulsants for women with pre-eclampsia. Cochrane Database
Syst Rev. 2003;(2):CD000025.
The Magpie Trial Collaboration Group. Do women with pre-eclampsia, and
their babies, benefit from magnesium sulphate? The Magpie Trial: a
randomised placebo-controlled trial. Lancet 2002; 359:1877–1890.
This was a most comprehensive study on magnesium sulphate that confirmed the
beneficial results of magnesium sulphate in relation to preeclampsia.
Livingston JC, Livingston LW, Ramsey R, et al. Magnesium sulfate in women
with mild preeclampsia: a randomised controlled trial. Am J Obstet Gynecol
2003; 101:217–220.
This interesting study raised doubt over whether widespread use of magnesium
sulphate in mild pre-eclampsia is of value.
17 Ferrer RL, Sibai BM, Mulrow CD, et al. Management of mild chronic
hypertension during pregnancy: a review. Obstet Gynecol 2000; 96:849–
18 Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug
therapy for mild to moderate hypertension during pregnancy. Cochrane
Database Syst Rev. 2001;(2):CD002252.
Magee LA, Duley L. Oral beta-blockers for mild to moderate hypertension
during pregnancy. Cochrane Database Syst Rev. 2003;(3):CD002863.
Benefits of beta-1-selective adrenoceptor blockers in the first trimester should be
carefully evaluated against the increased risk of low birth weight of baby.
20 Easterling TR, Carr B, Brateng DB, et al. Treatment of hypertension in
pregnancy: Effect of atenolol on maternal disease, preterm delivery and fetal
growth. Obstet Gynecol 2001; 98:427–433.
Bayliss H, Churchill D, Beevers M, Beevers DG. Anti-hypertensive drugs in
pregnancy and fetal growth: evidence for ‘pharmacological programming’ in
the first trimester? Hypertens Pregnancy 2002; 21:161–174.
An interesting study that highlighted the question of why b1-selective blockers
cause reduced fetal growth.
22 Brown MA, Buddle ML, Farrel T, Davis GK. Efficacy and safety of nifedipine
tablets for the acute treatment of severe hypertension in pregnancy. Am J
Obstet Gynecol 2002; 187:1046–1050.
23 Elatrous S, Nouira S, Ouanes Besbes L, et al. Short-term treatment of severe
hypertension of pregnancy: prospective comparison of nicardipine and
labetalol. Intensive Care Med 2002; 28:1281–1286.
Aali BS, Nejad SS. Nifedipine or hydralazine as a first line agent to control
hypertension in severe preeclampsia. Acta Obstet Gynecol Scand 2002;
This is a comparison of the two drugs used in severe preeclamptic women
presents results that would inspire other research groups to try to confirm if
nifedipine is a better alternative than hydralazine.
25 Duley L, Henderson-Smart DJ. Drugs for treatment of very high blood
pressure during pregnancy (Cochrane review). In: The Cochrane Library,
Issue 4. Chichester: John Wiley & Sons Ltd, 2003.
26 Keiseb J, Moodely J, Connolly CA. Comparison of the efficacy of continous
furosimeide and low dose dopamine infusion in preeclampisa/eclampis
related oliguria in the immediate postpartum period. Hypertens Pregnancy
2002; 21:225–234.
27 Pietrement C, Malot L, Santerne B, et al. Neonatal acute renal failure
secondary to maternal exposure to telmisartan, angiotensin II receptor
antagonist. J Perinatol 2003; 23:254–255.
Drugs used in hypertensive diseases 5

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